DE1271720B - Process for the preparation of L - (-) - beta-3, 4-dihydroxyphenyl-alpha-methyl-alanine - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY GERMAN #n PATENT OFFICE Int. Cl .:

C07c

EDITORIAL

German class: 12 q - 34

Number: 1271720

File number: P 12 71 720.3-42 (F 45772)

Filing date: April 9, 1965

Open date: 4th July 1968

It has already been suggested L-a-methyl-DOPA by cleavage of the 3,4-dimethoxybenzylmethylmalonic acid monomethyl ester with optically active bases in its antipodes and subsequent transfer the L - (+) - compound in l - (-) - /? - 3,4-dihydroxyphenyl-a-methyl-alanine (= a-methyl-DOPA).

In a further embodiment of this process, it has now been found that, instead of the 3,4-dimethoxybenzyl-methyl-malonic acid monomethyl ester also the 3,4-diallyloxybenzyl-methyl-malonic acid monomethyl ester split into its optical antipodes and the resulting L-compound into a-methyl-DOPA can convict.

The invention accordingly provides a process for the preparation of L-3,4-dihydroxyphenylu-methyl-alanine, which is characterized in that the 3,4-diallyloxybenzyl-methyl-malonic acid monomethyl ester the formula

CH ₂ = CH-CH ₇ O

CH ₇ = CH

COOCH ₃ CH ₂ -C-CH ₃

COOH

II

with optically active bases into its antipodes and then cleaves the D compound of the formula II by esterification with methylating agents into an optically inactive ester of the formula I

CH ₇ = CH-CH ₇ O

CH ₇ = CH-CH ₇ O

COOCH ₃

CH ₂ -C-CH ₃

COOCH ₃
I.

Process for the preparation of L - (-) - / Ö-3,4-dihydroxyphenyl-a-methyl-alanine

Applicant:

Farbwerke Hoechst Aktiengesellschaft formerly Master Lucius & Brüning, 6000 Frankfurt

Named as inventor:

Dr. Hans-Joachim Bohn, 6233 Kelkheim;

Dr. Günther Seidl,

6230 Frankfurt-Unterliederbach

into an L compound of the general formula IHa

COOR ₁ nC ₃ H ₇ - / V- CH ₂ -C- CH ₃

nC ₃ H ₇ O ^{NHR IIIa}

in which R denotes a hydrogen atom or a carbalkoxy group and R ₁ denotes a hydrogen atom or a methyl group, converts and, optionally without isolating the compound III a, splits or splits off the propyloxy groups simultaneously with an optionally present methyl ester and / or carbalkoxy group by the action of strong hydrohalic acids
b) into a compound of the general formula III

and this ester is converted back into the racemic starting compound by half-sided alkaline saponification of the formula II and the L compound of the formula II either

a) catalytically hydrogenated and the L-compound thus obtained the formula Ha

COOCH ₃
11-C ₃ H ₇ O - / V CH ₂ - C - CH ₃

nC, H ₇ O ^COOH » ^a

CH ₂ = CH-CH ₂ O

CH ₇ = CH-CH ₇ O

COOR ₁ V-CH ₂ -C-CH ₃

NH-R III

in which R and R _{1 have} the abovementioned meaning, and this compound III either

1. Treated with hydrohalic acids or 2. catalytically hydrogenated and the compound thus obtained of formula IIIa in turn treated with strong hydrohalic acids or

809 SU / 530

3. an allyloxy group due to the action of alkali hydroxide simultaneously with an optionally present methyl ester and / or carbalkoxy group split off and the compound of formula IV obtained in this way

CH ₃
CH ₂ -CH-CH ₂ O-] a - \ [

K VCH ₂ -C-COOH
HO-J \ = ^!

NH ₂ IV

either α) treated with hydrohalic acid or β) catalytically hydrogenated and the compound of the formula IVa thus obtained

CH ₃

, I.
V-CH ₂ -C-COOH

HO - J \ =

NH ₂

IVa

then treated with strong hydrohalic acids.

The dimethyl ester of formula I used as starting material can be z. B. in itself known Way obtained according to the following equation:

HO

CH ₂

CHO

/ COOCH ₃
^ COOCH

³ HO

OH

OH

COOCH ₃

COOCH ₃

1. CH ₂ = CHCH ₂ ClZNa ₂ CO ₃

2. CH ₃ X / CH ₃ ONa ^y

_ _CH _ _Q __ / V

CH ₇ = CH - CH - O

Half-sided saponification of the dimethyl ester of the formula I is carried out by adding one equivalent Alkali hydroxide or alkaline earth hydroxide, preferably sodium or potassium hydroxide, to one methanolic solution of the starting material.

It is also possible to add the calculated amount of water to a solution of the dimethyl ester of the formula I in a methanolic solution of sodium methylate. The Halbverseifung carried out at a temperature of 10 to 70 ° C within a time of ¹ Z ₂ to 15 hours, being required at lower temperatures, such as room temperature, longer time, while the Halbverseifung between 40 and 7O ^C C completed in a short time . For work-up, the solvent is distilled off, the residue is mixed with water and the reaction product is released by acidification with a strong mineral acid. The half-ester of the formula II can be extracted with a water-immiscible solvent. It has an asymmetric carbon atom and can therefore be broken down into the antipodes by salt formation with optically active bases. Alkaloids such as quinine, quinidine, cinchonine, cinchonidine, brucine, morphine, strychnine may be mentioned as bases;

The resolution is preferably carried out with quinine. For this purpose, solutions of equimolar amounts of the nx half-ester of the formula Ii and quinine are mixed and the quinine salt of the l - (+) - half-ester which has precipitated after standing for several hours is filtered off. ¹ l ₂ equivalent of the quinine required for complete salt formation can advantageously be replaced by the corresponding amount of a low molecular weight, optically inactive inorganic or organic base, such as sodium hydroxide, potassium hydroxide, ammonia, triethylamine, butylamine or morpholine.

The solvents used for the salt precipitation are predominantly anhydrous or water-containing lower alcohols and aqueous lower ketones, especially aqueous mixtures of methanol, ethanol or acetone as well as isopropanol or methyl ethyl ketone in question.

The water content can be between 5 and 95 ¹ Vo.

You can still use this quinine salt in the

Obtained way that one of the formula II to the saponification ¹ Z ₂ -AqUivalent quinine added without isolation of the Dx-monoester and the alkaline solution is neutralized by adding ¹ Z ₂ equivalents of a dilute aqueous acid, WJE hydrochloric acid, hydrobromic acid, nitric acid or acetic acid.

The quinine salts of the i .- (+) -methyl half esters of the formula II are suspended in water and, with stirring, with a slight excess of an acid such as hydrochloric acid. Hydrobromic acid, nitric acid or acetic acid, added, the t- ( + (half-ester of the formula II being obtained practically free of isomers.

After extraction with a water-immiscible solvent, the quinine is removed from the aqueous Phase by adding excess base. z. B. alkali hydroxide, precipitated and recovered.

Another possibility of breaking down the salt is that from the aqueous suspension first the quinine precipitated with alkali hydroxide and sucked off or with one immiscible with water organic solvent is extracted; then the alkaline solution becomes the optically pure L (+) half-ester of the formula II released by adding an acid and by extraction isolated.

The organic solvent present in the filtrate of the quinine salt precipitation is largely removed by distillation removed and the enriched d- (-) - half-ester of the formula II from the aqueous phase in the for the quinine salt of the L (+) half-ester isolated in the manner described.

The undesired isomer of the D series obtained in this way can be converted back into the symmetrical and thus optically inactive dimethyl ester of the formula I in a simple manner by esterification. The esterification with a methylating agent is preferably carried out so that the optically active Halbester with a dilute aqueous or aqueous methanolic solution or suspension of alkali or alkaline earth metal hydroxide or carbonate added is and between 20 and 70 ⁰ C with a methylating agent such as dimethyl sulfate, methyl toluene sulfonate , Methyl chloride, bromide or iodide, optionally under pressure, is reacted.

The optically inactive dimethyl ester of the formula I obtained in this way is, if appropriate after distilling off organic solvents, fed back to the half-sided saponification.

The L-half ester of the formula II can now according to the procedure listed under a) or b) (cf. the formula scheme) converted into a-methyl-DOPA will.

According to the method described under a), the L-half ester of the formula II is converted into the LS ^ -dipropyloxybenzyl-methylmalonic acid monomethyl ester of the formula II a by catalytic hydrogenation. The catalytic hydrogenation is carried out in a manner known per se in the presence of a catalyst of group VIII of the Periodic Table, such as palladium or platinum, or an active Raney catalyst, such as Raney nickel or Raney cobalt. The hydrogenation is carried out in a solvent, e.g. B. lower aliphatic alcohols such as methanol, ethanol, isopropanol or glacial acetic acid carried out. You can also hydrogenate in the shaking duck at room temperature or at higher temperatures of up to about 80 to 100 ^° C., optionally also under pressure. After filtering off the catalyst and concentrating the solution, the optically active half-ester of the formula Ha is obtained and converted into the process product.

This conversion takes place, for example, by degradation of the L-half ester of the formula II a via the intermediate isocyanate by exchanging the carboxy group for an amino function in Compounds of the formula UIa, the optical activity being fully retained. For this procedure the thermal degradation of the curbonic acid azide, either from the half-ester, is particularly suitable of the formula Ha by the action of inorganic acid chlorides, such as thionyl chloride, phosphorus trichloride or phosphorus oxychloride, and subsequent I reaction of the carboxylic acid chloride with an alkali / id can be obtained, particularly advantageously in a gentle manner by treating the trialkylammonium salt of the L-half ester of the formula II a with an alkyl chloroformate and then with an alkali azide.

The optically active carboxylic acid azide obtained in this way can, because of its relatively low nitrogen content, be subjected to thermolysis in a safe and easily controllable manner. For this purpose, the azide is added to a preheated solvent and heated until the evolution of gas has ceased. Lower alcohols, such as methanol, ethanol, propanol or butanol, and also acetic acid, hydrochloric acid, hydrobromic acid or mixtures thereof, are suitable as solvents. Furthermore, it is also possible to take up the carboxylic acid azide at room temperature in one of the solvents mentioned and to heat it slowly. A slight evolution of gas is at room temperature at the end of the desired reaction, however, it is advantageous to accelerate the reaction by heating at a temperature between 50 and 130 ⁰ C.

The "carbamic acid ester of the general formula IHa (R ₁ = CH ₃ , R = COOAIk) formed when using lower alcohols is fed directly to further saponification, optionally as a residue after distilling off the solvent. This reaction step can be carried out by heating the carbamic acid ester for several hours in a strong aqueous or alcoholic alkali metal hydroxide solution. After neutralization, the compound III a (R = R ₁ = H) is isolated. If, on the other hand, the carbamic acid ester III a (R = COOAIk, R ₁ = CH ₃ ) is treated with an alkali metal hydroxide solution under milder conditions (For example, standing for several hours at 25 ° C.), the compound III a, in which R is COOAIk and R _{1 is} a hydrogen atom, can be isolated.

The conversion of the carboxyl group in the half-ester of the formula Ha into an amino group substituted by R. can also be carried out using other degradation methods instead of azide degradation, be mentioned z. B. the Hofmann dismantling.

The compound III a (R = R ₁ = H) is then treated in a manner known per se by heating with concentrated aqueous hydrohalic acids, preferably with concentrated aqueous hydrobromic acid, optionally under pressure. To prevent autoxidation, it is advisable to work in the presence of a protective gas such as nitrogen or carbon dioxide. After the reaction has ended, the process product is obtained, if appropriate after concentration of the solution, by neutralization with dilute aqueous bases, such as sodium hydroxide, potassium hydroxide, ammonia or triethylamine. After cooling, the process product is isolated by suction.

The process product can also be obtained by carrying out the above-described treatment with hydrobromic acid on an intermediate of the general formula III a (R = COOAIk, R ₁ = H · CHj). It is also possible to carry out the azide degradation in concentrated hydrohalic acid and, after the evolution of gas has ceased, the reaction solution

^(l i eral hours m cooking.

According to the procedure described under b), the L compound of the formula II is first in the 3,4-diallyloxyphenylalanine derivative of the general

Formula III transferred. This degradation takes place in the manner described above for the 3,4-dipropyl compound Way. The diallyloxyphenylalanine derivative of the formula III obtained in this way can now be used in various ways be transferred into the process product. According to the manner described under b) 1. the Compounds of the formula III treated directly with hydrohalic acids, the process product being obtained directly in one step. These Acid treatment takes place in the manner described for the compounds of general formula III a instead of.

The compounds of the formula III can also be converted into compounds according to b) 2. by catalytic hydrogenation the general formula III a are converted. The hydrogenation conditions correspond those above for the hydrogenation of the 3,4-diallyloxybenzylmalonic acid half-ester in the corresponding 3,4-dipropyloxy compound described conditions. the Compounds of the general formula III a thus obtained are, as written above, by treatment converted into the process product with acids.

Finally, it is also possible according to b) 3., from compounds of the formula III by treatment with Alkali hydroxides only split off an allyl group, while at the same time any methyl ester group that may be present or carbalkoxy group or these two groups are split off.

This implementation is carried out under vigorous conditions; the alkali hydroxide is used in more than a 3-fold excess. Suitable solvents are water or alcohols such as methanol, ethanol, propanol, butanol, amyl alcohol, benzyl alcohol, glycol, glycerine, propylene glycol or glycol monomethyl ether. The reaction mixture is heated to a temperature between 70 and 150 ⁰ C. If necessary, the solvent can also be distilled off and the residue is heated to a temperature between 100 and 160 ⁰ C. To isolate the reaction product, the residue is taken up in water and neutralized with acids. The compound IV precipitates out and can be filtered off.

The monoallyloxy compounds of the general formula IV obtained can now in turn either be converted into α-methyl-DOPA by direct acid treatment with hydrohalic acids in the manner described above (procedure a) or they can be catalytically converted to the monopropyloxy compound of the general formula in the manner described under β) IVa are converted, whereupon the propyloxy group is then split off by the action of strong hydrohalic acids in the manner described for the compounds of the formula III a.

The process is chemically peculiar because it has been shown that in the resolution of the Methyl half ester II, surprisingly, is quinine

CH ₂ = CH-CH ₂ O

CH ₂ = CH - CH ₂ O salt of the desired L series crystallized in practically isomer-free form and in good yield. In contrast, when higher monoalkyl esters are used, the quinine salts of the D series are usually obtained; the L compound must then be isolated from the filtrate and is only obtained in an optical purity of about 50 to 60%.

It has also been found that the racemic monomethyl ester Ha, which is produced by catalytic hydrogenation of the racemic half ester II is obtained when attempting the resolution under analogous Conditions only gives a poorly crystallizing quinine salt of unsatisfactory optical purity. The main advantage of the new process for the production of L-a-methyl-DOPA is that the L-half ester of the formula II in the resolution of the racemate directly as a sparingly soluble salt in optically pure form and in good yield. Another purification of the salt by recrystallization not necessary. The used fission base can be recovered with practically no loss will. When the salt with the optically active base is broken down by acids or bases, too no racemization observed in the presence of polar solvents.

The D-half ester can be obtained from the resolution filtrate and by simple esterification be recycled back into the optically inactive dimethyl ester of the formula I.

In contrast, in the previously known processes for the resolution of 3-aryl-2-methyl-2-aminopropionitriles (cf. Belgian patent 633 417), the compounds of the D series are precipitated with the aid of the natural and thus easily accessible isomers of optically active acids , while the desired L-amino nitriles are obtained from the filtrate only in optically impure form. The subsequent purification by recrystallization is an additional process step that results in yield losses. The release of the L-aminonitrile from the salt requires special precautionary measures because of the optical lability of the intermediate product.
If, on the other hand, the resolution is carried out at a later stage (cf. German Auslegeschrift 1 171 931), the desired L compound does crystallize out; However, the D-compound obtained as a by-product has to be returned to the arylacetone used as the starting material in a multistage process (cf. Dutch patent application 6400 810).

The process product is a valuable therapeutic agent, in particular as a means against Hypertension is used. It can optionally in the form of its salts with physiologically compatible Acids can be processed into tablets or injection solutions with the usual additives and carriers. It can also be mixed with other therapeutically valuable substances.

CH,

COOCH ₃
C-CH,

• COOH

1 COOR ₁ CH ₂ = CH-CH ₂ O / ^ CH ₂ -C-CH ₃

CH, = CH-CH ₇ O

CH ₂ = CH-CH ₂ O-

HO-J ^ =

NH-R
III

NH ₂
IV

CH ₃
CH ₂ -C-COOH

NH ₂
IVa

example 1
a) 3,4-diallyloxybenzyl-methyl-malonic acid

monomethyl ester

CH,

CH ₂ -C-COOCH ₃

COOH

CH ₂ = CH-CH ₂ O
CH ₂ = CH-CH ₂ O

C ₁₈ H ₂₂ O ₆ : MS 334.4.

104.5 g (0.3 mol) of dimethyl 3,4-diallyloxybenzylmethylmalonate are in 750 ml of methanol with 150 ml of 2N NaOH (0.3 mol) for 1 hour Refluxed. After removing the solvent in vacuo, the residue is dissolved in water, the solution is filtered with charcoal and adjusted to pH 1 with hydrochloric acid. The separated oil is in Methylene chloride was taken up, the solution was washed with water, dried and evaporated in vacuo. 81 g of a light yellow oil (80.9%) remain

b) Quinine salt of 3,4-diallyloxybenzyl-methylmalonic acid monomethyl ester

39.7 g (0.124 equivalents) of 3,4-diallylyloxybenzylmethylmalonic acid monomethyl ester are dissolved in methanol with 31 ml (0.062 mol) of 2N NaOH and 20.1 g (0.062 mol) of quinine. The mixture is mixed with water and stored in a refrigerator at +4 ⁰ C. The crystals are then filtered off, washed with a little methanol-water (1 + 1) and dried. The substance weighs 31.2 g (81% of theory). F. = 138 ° C. The mother liquor is concentrated in vacuo, the residue is partitioned between 2N HCl and methylene chloride, the organic phase is separated off, dried and evaporated in vacuo. The residue weighs 23 g.

c) re-esterification of the D compound

The 23 g of the residue obtained according to b) are dissolved in 36 ml of 2N NaOH and treated dropwise at 45 to 50 ° C. with 13.7 g of dimethyl sulfate. Then 12.5 g of K ₂ CO _{3 are} added. After a further addition of 13.7 g of dimethyl sulfate, the mixture is stirred on the steam bath for 30 minutes. After cooling, it is extracted with ether, the organic phase is washed with 1N NaOH and then with H ₂ O, dried and concentrated. Yield: 20.2 g of dimethyl ester I = 84.5% of theory.

d) 1- (+) - 3,4-diallyloxybenzyl-methyl-malonic acid monomethyl ester

104 g of the quinine salt obtained according to b) (0.158 mol) are shaken with 500ml 2N HCl and 500ml ether, the phases are separated, the aqueous solution is extracted again with ether and the combined ethereal Solutions dried. After the ether has been stripped off, 50.7 g of L - (+) - 3,4-diallyloxybenzylmethylmalonic acid monomethyl ester remain as a residue (= 98.6% of theory).

e) 1- (+) - 3,4-Dipropyloxybenzyl-methylmalonic acid monomethyl ester

73.5 g (0.22MoI) in 50 ml of dioxane are with Palladium hydrogenated as a catalyst at room temperature and normal pressure. The solution is filtered and evaporated in vacuo. The residue is 72 g = 96.8% of theory L - (+) - 3,4-dipropyloxybenzyl - methyl - malonic acid - monomethyl ester.

M9 5M / 530

f) L - (-) - α-methyl-DOPA

72.0 g (0.213 mol) of the L - (+) - 3,4-dipropyloxybenzyl - methyl - malonic acid - monomethyl ester obtained are dissolved in 150 ml of acetone and 25.8 g (0.256 mol) of triethylamine in 150 ml of acetone, 25, 4 g (0.234 mol) of ethyl chloroformate in 150 ml of acetone and, after 45 minutes, reacted with 23.5 g (0.362 mol) of sodium azide in 7.5 ml of H ₂ O. After 1 hour's stirring is shaken with water and methylene chloride, the organic phase dried and evaporated at 40 ⁰ C bath temperature under reduced pressure. The crude azide is added dropwise to 500 ml of 20% HCl at 95 ° C. and heated for 1 hour. The solution is evaporated and the residue is refluxed with 500 ml of 48% hydrobromic acid under nitrogen for 3 hours. After concentration, the residue is dissolved in water, the solution is filtered with charcoal, adjusted to pH 6 with diethylamine and saturated _{with SO 2.} The solution is concentrated in vacuo and, when crystallization begins, placed in ice, filtered and the substance is washed with a little ice water and acetone. 33.0 g = 67% La-methyl-DOPA, m.p. = 298 ° C. [a] !, ⁰ = 4 ° (10 η HCl, 2% solution) are obtained.

Example 2

a) L - ^ - 3,4-diallyloxyphenyl-a-methyla-carbethoxyaminopropionic acid methyl ester

30th

33.4 g (0.1 mol) of L-S ^ -diallyloxybenzyl-methyl-malonic acid monomethyl ester from Example 1, d) are according to the method described in Example 1, f) with 12 g (0.12MoI) triethylamine, 12 g (0.11 mol) Ethyl chloroformate and 11g sodium azide (0.17 mol) implemented. The crude azide is refluxed in 100 ml of absolute ethanol for 1 hour, 2.3 liters of nitrogen are released. After concentrating the solution, 35.2 g (= 93.5% of theory) L- (3-3,4-diallyloxyphenyl-a-methyla-carbäthoxyamino-propionic acid methyl ester.

b) Allyloxy-hydroxyphenyl-a-methyl-alanine

45

32 g of the urethane obtained according to Example 2, a) are mixed with 100 ml of ethanol and 80 ml of 50% strength KOH refluxed for 1 hour, then the alcohol is distilled off and the residue for 3 hours further heated at an internal temperature of 120 ° C. After cooling, the mixture is made up with glacial acetic acid Set pH 6 and cooled. The precipitate is filtered off, washed with acetone-ether and dried. Mp = 229 to 230 ° C (decomposition).

55 c) La-methyl-DOPA

17 g of the allyloxy-hydroxyphenyl-a-methyl-alanine obtained according to b) are refluxed for 1 hour _{in 125 ml of 48% hydrobromic acid under N 2.} After concentration, the residue is dissolved in water, the solution is filtered with charcoal and adjusted to pH 6 with diethylamine; it is saturated with SO ₂ , filtered and slowly concentrated. When crystallization begins, it is placed in ice for 3 hours, filtered off with suction and washed with a little ice water and then with a lot of acetone. Yield: 12.75 g of L-α-methyl-DOPA (85% of theory).

Claims (3)

Claim: A process for the preparation of L-3,4-dihydroxyphenyl-a-methyl-alanine, characterized in that the 3,4-diallyloxybenzylmethyl malonic acid monomethyl ester of the formula II CH9 = CH-CH, O CH, = CH- CH9O COOCH3 CH2-C-CH, COOH with optically active bases splits into its antipodes and then cleaves the D compound of the formula II by esterification with methylating agents into an optically inactive ester of the formula I COOCH3 CH7 = CH-CH9O CH2 = CH-CH2O COOCH3 I converted and this ester is converted back into the racemic starting compound of the formula II by partial alkaline saponification and the L compound of the formula II is either a) catalytically hydrogenated and the L compound of the formula Ha COOCH3 COOH Ha thus obtained is converted into an L compound of the general formula III a COOR1 CH2-C-CH3 NHR III a in which R is a hydrogen atom or a carbalkoxy radical and R1 is a hydrogen atom or a methyl group, and, optionally without isolating the compound III a, converts the P ropylenoxy groups at the same time with an optionally present methyl ester and / or carbalkoxy group by the action of strong hydrohalic acids or b) converts into a compound of the general formula III CH2 = CH-CH2O CH2 = CH-CH2O in which R and R1 have the meaning given above, and this compound III either 1. Treated with hydrohalic acids or 2. catalytically hydrogenated and the compound of formula III a thus obtained in turn with treated with strong hydrohalic acids or 3. by the action of alkali hydroxide, an allyloxy group at the same time as an optionally splitting off existing methyl ester and / or carbalkoxy group and the compound of formula IV obtained in this way CH ₂ = CH-CH ₂ O-] CH, 10 , / VcH ₂ -C-COOH HO-J \ = / NH ₂ IV either α) treated with hydrohalic acids or ß) catalytically hydrogenated and the compound of formula IVa thus obtained CH ₃ K V-CH ₂ -C-COOH HO-J \ = / I NH, then treated with strong hydrohalic acids. 809 561/530 6. ti O Bundetdruckerei Berlin